Inhibitors of slow reacting substance of anaphylaxis

ABSTRACT

Novel compounds and compositions which inhibit SRS-A in mammals are disclosed. Methods for preparing said compounds and compositions and methods for their use for treating allergic reactions, inflammation and for reducing the severity of myocardial infarction resulting from heart attack are disclosed. 
     Useful intermediates for preparing said compounds are also disclosed.

This is a continuation of application Ser. No. 632,143 filed 7/18/84,now abandoned.

SUMMARY OF THE INVENTION

The invention sought to be patented in its chemical compound aspect is

A compound having the structural formula I, II or III wherein: ##STR1##

T is straight or branched chain alkyl having from 7-15 carbon atomswhich may optionally contain from 1-3 non-cumulative double or triplebonds;

U is --CH₂ --CH₂ --, --CH═CH-- or --C.tbd.C--;

V is straight or branched chain alkylene having from 1 to 4 carbon atomsor is a direct bond;

W and W¹ may be the same or different and are O or S(O)_(m) [wherein mis 0, 1 or 2];

X and X¹ may be the same or different and are straight or branched chainalkylene having from 2 to 12 carbon atoms which may optionally containfrom 1 to 3 non-cumulative double or triple bonds and which may beoptionally substituted with the group --NHR^(a) [wherein R^(a) ishydrogen, alkyl having from 1 to 6 carbon atoms, COCF₃, CO(CH₂)₂CH(NH₂)CO₂ H, or SO₂ R^(b) (wherein R^(b) is alkyl having from 1 to 6carbon atoms or CF₃)];

R¹ is hydrogen or straight or branched chain alkyl having from 1-6carbon atoms;

R² and R³ may be the same or different and are CH₂ OR^(c) [wherein R^(c)is hydrogen, carboxylic acyl having from 1 to 6 carbon atoms,tetrahydropyran-2-yl or COCH₂ CH₂ CO₂ H], CHO, 2-tetrazolyl, COR^(d)[wherein R^(d) is hydroxy, alkoxy having from 1 to 6 carbon atoms, OCH₂OC(O)C(CH₃)₃, NHR^(e) (wherein R^(e) is hydrogen, alkyl having from 1 to6 carbon atoms or CH₂ CO₂ H)] or SO₃ H, with the proviso that at leastone of R² and R³ is 2-tetrazolyl or carboxyl; ##STR2##

T, U, V, W, X, R² and R³ are defined above;

Y is straight or branched chain alkylene having from 1 to 12 carbonatoms which may optionally be substituted with the group OR^(c) [whereinR^(c) is defined above] and may optionally contain from 1 to 3non-cumulative double or triple bonds; ##STR3##

T, U, V, R² and R³ are defined above;

Z and Z¹ may be the same or different and are straight or branched chainalkylene having from 1 to 12 carbon atoms which may optionally containfrom 1 to 3 non-cumulative double or triple bonds;

R⁴ is hydrogen, hydroxyl, or is combined with Z to form a double bond asindicated by the dashed line "a" or a cyclopropyl ring as indicated bythe dashed lines "b".

Preferred values for the above-defined substituents are as follows:

T is straight chain alkyl having 7-15 carbon atoms;

U is --C.tbd.C--;

V is a direct bond;

W is O or S;

W¹ is O or S;

X is alkyl having from 2 to 8, more preferably 2 to 6 carbon atoms;

X¹ is alkyl having from 2 to 8, more preferably 2 to 6 carbon atoms;

R¹ is hydrogen;

R² is carboxyl;

R³ is carboxyl;

Y is alkyl having from 2 to 6 carbon atoms;

Z is alkyl having from 2 to 6 carbon atoms;

Z¹ is alkyl having from 2 to 6 carbon atoms;

Z¹ is alkyl having from 2 to 6 carbon atoms;

R⁴ is hydrogen, hydroxyl or is combined with Z to form a double bond.

A preferred subgenus of compounds is a compound having structuralformula I, II or III wherein the substituents T--U--V-- are combined toform the n-1-tetradecyn-1-yl group, i.e. n--C₁₂ H₂₅ C.tbd.C--.

An additional preferred subgenus of compounds is a compound havingstructural formula I, II or III wherein the substituents R² and R³ maybe the same or different and are COR^(d) wherein R^(d) is defined above.

Preferred species of the invention are those having the following names:

butanoic acid, 4,4'-[2-pentadecynylidenebis(oxy)]bis-;

hexanoic acid, 6,6'-[2-pentadecynylidenebis(oxy)]bis-;

(±)-pentanoic acid, 4,4'-[2-pentadecynylidenebis(oxy)]bis-;

(±)-heptanoic acid, 6,6'-[2-pentadecynylidenebis(oxy)]bis-;

butanoic acid, 4-[[1-(4-hydroxybutoxy)-2-pentadecynyl]oxy]-;

butanoic acid, 4,4'-[2-pentadecynylidenebis(thio)]bis-;

hexanoic acid, 6,6'-[2-pentadecynylidenebis(thio)]bis-;

butanoic acid, 4,4'-[tridecylidenebis(oxy)]bis-;

butanoic acid, 4,4'-[pentadecylidenebis(oxy)]bis-;

(±)-hexanoic acid, 5,5'-[2-pentadecynylidenebis(oxy)]bis-;

(±)-6-[(2-carboxyethyl)thio]-7-eicosynoic acid;

(±)-6-[(3-carboxypropyl)thio]-7-eicosynoic acid;

(+) and (-)-6-[(5-carboxypentyl)thio]-7-eicosynoic acid;

(±)-6-[(5-carboxypentyl)oxy]-7-eicosynoic acid;

(±)-6-[[2-[(N-trifluoroacetyl)amino]ethyl]thio]-7-eicosynoic acid:

(±)-6-[[2-carboxy-2-[(trifluoroacetyl)amino]ethyl]thio]-7-eicosynoicacid;

6-hydroxy-6-(1-tetradecynyl)undecanedioic acid;

6-(1-tetradecynyl)undecanedioic acid;

6-(1-tetradecynyl)undec-5(E) and (Z)ene dioic acids;

(±)-pentanoic acid, 4,4'-[2-pentadecynylidenebis(thio)]bis-;

6-tetradecyl-6-hydroxy-undecanedioic acid;

2-butynoic acid, 4,4'-[2-pentadecynylidenebis(oxy)]bis-;

methanesulfonamide,N,N'-[2-pentadecynylidenebis[oxy(5-methyl-5,1-pentanediyl)]]bis-; and

hexanoic acid,5-[[1-[(5-amino-1-methyl-5-oxopentyl)oxy]-2-pentadecynyl]oxy].

The invention sought to be patented in its pharmaceutical compositionaspect is a composition which comprises a compound having the structuralformula I, II or III in combination with a pharmaceutically acceptablecarrier.

The invention sought to be patented in its first pharmaceutical methodaspect is a method for treating allergic reactions in a mammal, whichcomprises administering the above-defined composition to said mammal.

The invention sought to be patented in its second pharmaceutical methodaspect is a method for treating inflammation in a mammal, whichcomprises administering the above-defined composition to said mammal.

The invention sought to be patented in its third pharmaceutical methodaspect is a method for reducing the severity of myocardial infarctionresulting from heart attack in a mammal, which comprises administeringthe above-defined composition to said mammal.

DESCRIPTION OF THE INVENTION

The compounds of the invention having structural formula I may beprepared by reacting a compound having structural formula X with acompound having the structural formula XI,

    T--U--V--CR.sup.1 (OR').sub.2                              X

    HWXR.sup.2                                                 XI

wherein T, U, V, W, X, R¹ and R² are as defined herein and R' is anyconvenient alkyl group, preferably ethyl. The carbonyl compound whichcorresponds to compound X, i.e., T--U--V--COR¹, may optionally beutilized in this reaction in place of compound X. This reaction ispreferably carried out under conditions whereby the reaction-producedalcohol, R'OH, or water is continuously removed as it is formed. Thiscontinuous removal may be accomplished by azeotropic distillation usinga solvent such as benzene or toluene. The reaction proceeds best whencatalyzed by acid, e.g. p-toluenesulfonic acid may be utilized; When anexcess (i.e. 2 equivalents or more) of reactant XI is utilized,compounds having structural formula I wherein --W--X--R² and --W¹ --X¹--R³ are equivalent will be produced. When compounds having structuralformula I wherein --W--X--R² and --W¹ --X¹ --R³ are different aredesired, the reaction may be accomplished in two separate stepsutilizing one equivalent of the desired reactant, XI, in each step. Inan additional method, a compound having structural formula I where W andW¹ are both oxygen may be treated with one equivalent of a compoundhaving structural formula XI wherein W is sulfur to thereby displaceeither the W--X--R² or the W¹ --X¹ --R³ substituent. For purposes ofthis procedure, the W--X--R² and W¹ --X¹ --R³ substituents of startingcompound I should ideally be equivalent. This procedure is convenientlycarried out using an acid catalyst such as boron trifluoride. Compoundshaving structural formula I wherein W and W¹ are sulfur may be oxidizedto the corresponding sulfoxide or sulfone by known procedures.

Compounds having structural formula II may be prepared from a compoundhaving formula XII, wherein T, U, V, Y and R³ are defined above.

    T--U--V--CH(OH)YR.sup.3                                    XII

Compounds having structural formula II wherein W is sulfur may beprepared by first converting the hydroxyl substituent of compound XII toa more readily displacable substituent, e.g. the methane sulfonic acidester, XIII,

    T--U--V--CH(OSO.sub.2 CH.sub.3)YR.sup.3                    XIII

or to the corresponding bromo or an activated phosphorous substituent.

The conversion of XII to XIII may be carried out by treating XII withmethane sulfonyl chloride under standard conditions. Compound XIII maythen be treated with a compound having structural formula XIV.

    HS--X--R.sup.2                                             XIV

using known conditions to produce the desired compounds havingstructural formmula II wherein W is sulfur. The sulfur atom maythereafter be oxidized to the corresponding sulfoxide or sulfone byknown procedures if desired.

Compounds having structural formula II wherein W is oxygen may beprepared from compound XIII in a similar manner by using the alcohol XV

    HO--X--R.sup.2                                             XV

Alternatively, compound XII may be converted to compound II wherein W isoxygen by direct alkylation on the hydroxyl oxygen atom. Thus, forexample, XII may be treated with a base such as sodium hydride to formthe corresponding sodium salt of the alcohol, XVI.

    T--U--V--CH(ONa)YR.sup.3                                   XVI

This salt may next be treated with a halide compound, for example, aniodo compound such as IXR² to produce the compounds having structuralformula II wherein W is oxygen.

Compounds having structural formula III may be prepared by reacting ananion derived from a compound having structural formula XVII,

    T--U--V--H                                                 XVII

i.e. compound XVIII

    T--U--V.sup.- M+                                           XVIII

wherein M+ is a metal cation such as the lithium cation, or anequivalent complex metal cation, e.g. MgBr⁺ with a carbonyl compoundhaving structural formula XIX ##STR4## using known procedures. Thisreaction will produce compounds having structural formula III wherein R⁴is a hydroxyl group. This tertiary alcohol function may thereafter beconverted to other R⁴ substituents by known methods if desired. Forexample, treatment of the tertiary alcohol with diethylaminosulfurtrifluoride will produce the corresponding compound wherein R⁴ isfluorine. The tertiary alcohol may be dehydrated to produce a compoundwherein R⁴ and Z are combined to form a double bond, i.e. a compoundhaving structural formula III wherein the dashed line "a" indicates adouble bond. This double bond compound may be reduced to produce thecompounds wherein R⁴ is hydrogen, or it may be reacted with methylenecarbene to produce the corresponding cyclopropyl compounds, i.e. acompound having structural formula III wherein the dashed lines "b"indicate the completion of a cyclopropyl ring.

In certain of the above-described reactions certain substituents mayhave to be protected in order to avoid unwanted reactions. Thus, forexample, certain of the R² and R³ substituents may be protected by artrecognized methods. In addition, certain of the groups, R² and R³ may bemodified, if desired, by known procedures. Thus, for example, a compoundwherein R² is CH₂ OH may be converted to a compound wherein R² is CO₂ Hby oxidation or to a compound wherein R² is CH₂ OCOCH₃ by acylation.

For purposes of completeness, the following abbreviated reactionsequence is utilized to exemplify a process for performing selectivereactions where multiple sites of unsaturation are present. Other suchsequences are known in the art. ##STR5##

In the above abbreviated reaction sequence, THP indicates the2-tetrahydropyranyl radical. Double bonds can be regiospecificallyincluded or excluded by proper choice of carbon to carbon bond formingreactions and reagents which will be known to those skilled in the art.

The above-described starting materials are either known compounds orpreparable from known compounds by art-recognized methods.

Thus, compound X is an acetal or ketal, which compounds are preparablefrom the corresponding aldehyde or ketone by well known methods. In analternate method, a compound such as XX may be reacted with anorthoester such as ethyl orthoacetate by known methods to produce theacetal XXI. ##STR6##

Compounds having structural formula XII are secondary alcohols which maybe prepared, for example, by the reaction of a Grignard reagent such asXXII with an aldehyde such as XXIII.

    T--U--V--MgBr                                              XXII

    OHCYR.sup.3                                                XXIII

Known equivalent reactants to XXII such as lithium reagents, e.g. XXIV,may also be utilized.

    C.sub.12 H.sub.25 C.tbd.CLi                                XXIV

Certain compounds of the invention form pharmaceutically acceptablesalts with any of a variety of inorganic and organic bases. Suitablebases for purposes of the invention, are those which formpharmaceutically-acceptable salts such as sodium hydroxide, sodiumcarbonate, sodium bicarbonate, potassium hydroxide, calcium hydroxide,ammonia and amines. The salt forms may be converted back to theirrespective acid forms by treatment with an acid such as dilutehydrochloric acid. The acid forms and their respective salts differ incertain physical properties such as solubility but they are otherwiseequivalent for purposes of the invention.

Certain compounds of the invention form pharmaceutically acceptablesalts with organic and inorganic acids. Examples of suitable acids forsalt formation are hydrochloric, sulfuric, phosphoric, acetic, citric,oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic,methanesulfonic, and the like. The salts are prepared by contacting thefree base form with a sufficient amount of the desired acid to produce asalt in the conventional manner. The free base forms may be regeneratedby treating the salt form with a base. For example, dilute aqueous basesolutions may be utilized. Dilute aqueous sodium hydroxide, potassiumcarbonate, ammonia, and sodium bicarbonate solutions are suitable forthis purpose. The free base forms differ from their respective saltforms somewhat in certain physical properties such as solubility inpolar solvents, but the salts are otherwise equivalent to theirrespective free base forms for purposes of the invention.

The compounds of the invention may exist in unsolvated as well assolvated forms, including hydrated forms. In general, these solvatedforms with pharmaceutically acceptable solvents such as water, ethanoland the like are equivalent to the unsolvated forms for purposes of theinvention.

Certain compounds of the invention may exist in isomeric forms. Theinvention contemplates all such isomers both in pure form and inadmixture, including racemic mixtures.

The compounds of this invention can be used to treat allergy causeddiseases and their preferred use is for treating allergic chronicobstructive lung diseases. Chronic obstructive lung disease as usedherein means disease conditions in which the passage of air through thelungs is obstructed or diminished such as is the case in asthma,bronchitis and the like.

The anti-allergy effects of the compounds of this invention may beidentified by tests which measure a compound's inhibition of leukotrieneC₄ induced contraction of lung smooth muscle. The substance leukotrieneC₄ is a component of slow reacting substance of anaphylaxis (SRS-A). Forexample, the compound hexanoic acid,6,6'-[2-pentadecynylidenebis(oxy)]bis- was found to inhibit leukotrieneC₄ contractions of lung smooth muscle in such a test procedure in vitroat a concentration of 10⁻⁵ Molar. Said compound was also found toinhibit leukotriene C₄ induced bronchospasm in guinea pigs in vivo at anintratracheal dose of 0.5 mg/kg or intravenous dose of 10 mg/kg.

Measurement of inhibition of leukotriene C₄ contractions in vitro

A guinea pig is killed and the lung is removed. The trachea, bronchi andlarge blood vessels are removed and discarded. Strips of long parenchymaare prepared from the lower lobes of the lung. The strips are suspendedin a heated organ bath containing 10 ml of oxygenated Tyrodes solution.Isometric tension is measured. A contractile response to 10⁻⁸ Molarleukotriene C₄ is generated in the absence and presence of test compoundand the percent inhibition produced by the test compound is calculated.

Measurement of inhibition of leukotriene C₄ bronchospasm in guinea pigsin vivo

Fasted male guinea pigs are anesthetized with dialurethane and preparedfor the measurement of intratracheal pressure as modified from H.Konzett and R. Rossler, Nauyn-Schmeidebergs Arch Exp Path Pharmakol 195:71-74, 1940. A bronchospasm [as measured by the increase inintratracheal pressure] is induced by the intratracheal administrationof 0.3 ug of leukotriene C₄ delivered in 0.1 ml of isotonic salinesolution. Test compound is administered either 10 min [intravenous] or 5min [intratracheal] before the administration of leukotriene C₄. Thebronchospasm to leukotriene C₄ is measured and a percent inhibition bythe test compound is calculated.

When administered orally the compounds of the invention are active atdoses from about 10 to 500 mg/kg of body weight; when administeredparenterally, e.g., intravenously, the compounds are active at dosagesfrom about 0.1 to 10 mg/kg body weight; when administered by inhalation(aerosol or nebulizer) the compounds are active at dosages of about 0.1to 5 mg per puff, one to four puffs may be taken every 4 hours.

The compounds of this invention are also useful for the treatment ofinflammation. The anti-inflammatory use of the compounds of the presentinvention may be demonstrated by the Reversed Passive Arthus Reaction(RPAR) Synovitis technique as set forth below using male Lewis rats(obtained from Charles River Breeding Laboratories) weighing 200-250grams. The potency of the compounds is determined using indomethacin asthe standard. On the basis of the test results, an oral dosage range ofabout 10 milligrams per kilogram of body weight per day to about 500milligrams per kilogram of body weight per day in divided doses taken atabout 4 hour intervals is recommended.

RPAR Synovitis Technique

A Lewis rat is dosed orally with drug or placebo one hour prior tointravenous administration of 2.28 mg of bovine serum albumin (BSA) in0.2 cc of pyrogen-free saline followed by the intraarticular injectionof 0.54 mg of rabbit anti-BSA antibody in 0.03 cc of pyrogen-free salineinto one knee joint. The contralateral knee is injected with 0.03 cc ofpyrogen-free saline. All injections are made with the animal under lightether anesthesia. Three hours later the rat is again dosed orally withdrug or placebo. All drug doses are split. That is, one-half of the doseis administered before lesion induction and one-half is administeredafter lesion induction.

The following morning (about 17 hours after lesion induction) the rat iskilled and both knee joints are exposed. The subpatellar areolar tissuewith attendant synovium is excised and weighed. Differences between theweight of antibody and saline injected knees are considered to representthe inflammatory response for each animal (delta synovial weight).Differences in delta synovial weight between lesion controls anddrug-treated rats are evaluated for statistical significance with ananalysis of variance. Relative potencies are determined with a linearregression analysis.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders or tablet disintegrating agents; it can also be an encapsulatingmaterial. In powders, the carrier is a finely divided solid which is inadmixture with the finely divided active compound. In the tablet theactive compound is mixed with carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired. The powders and tablets preferably contain from 5 or 10 toabout 70 percent of the active ingredient. Suitable solid carriers aremagnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin,dextrin, starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter and the like.The term "preparation" is intended to include the formulation of theactive compound with encapsulating material as carrier providing acapsule in which the active component (with or without other carriers)is surrounded by carrier, which is thus in association with it.Similarly, cachets are included. Tablets, powders, cachets and capsulescan be used as solid dosage forms suitable for oral administration.

For preparing suppositories, a low melting wax such as a mixture offatty acid glycerides or cocoa butter is first melted, and the activeingredient is dispersed homogeneously therein as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool and thereby solidify.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection. Liquid preparations can also be formulated insolution in aqueous polyethylene glycol solution. Aqueous solutionssuitable for oral use can be prepared by adding the active component inwater and adding suitable colorants, flavors, stabilizing, sweetening,solubilizing and thickening agents as desired. Aqueous suspensionssuitable for oral use can be made by dispersing the finely dividedactive component in water with viscous material, i.e., natural orsynthetic gums, resins, methylcellulose, sodium carboxymethylcelluloseand other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions. These particular solid form preparations aremost conveniently provided in unit dose form and as such are used toprovide a single liquid dosage unit. Alternately, sufficient solid maybe provided so that after conversion to liquid form, multiple individualliquid doses may be obtained by measuring predetermined volumes of theliquid form preparation as with a syringe, teaspoon or other volumetriccontainer. When multiple liquid doses are so prepared, it is preferredto maintain the unused portion of said liquid doses at low temperature(i.e., under refrigeration) in order to retard possible decomposition.The solid form preparations intended to be converted to liquid form maycontain, in addition to the active material, flavorants, colorants,stabilizers, buffers, artificial and natural sweeteners, dispersants,thickeners, solubilizing agents and the like. The solvent utilized forpreparing the liquid form preparation may be water, isotonic water,ethanol, glycerine, propylene glycol and the like as well as mixturesthereof. Naturally, the solvent utilized will be chosen with regard tothe route of administration, for example, liquid preparations containinglarge amounts of ethanol are not suitable for parenteral use.

Preferably, the pharmaceutical preparation is in unit dosage form. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, for example, packeted tablets, capsules and powders invials or ampoules. The unit dosage form can also be a capsule, cachet ortablet itself or it can be the appropriate number of any of these inpackaged form.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from 1 mg to 100 mg according to the particularapplication and the potency of the active ingredient. The compositionscan, if desired, also contain other therapeutic agents.

The dosages may be varied depending upon the requirements of thepatient, the severity of the condition being treated and the particularcompound being employed. Determination of the proper dosage for aparticular situation is within the skill of the art. Generally,treatment is initiated with smaller dosages which are less than theoptimum dose of the compound. Thereafter, the dosage is increased bysmall increments until the optimum effect under the circumstances isreached. For convenience, the total daily dosage may be divided andadministered in portions during the day if desired.

EXAMPLE 1 2-PENTADECYNYL ALDEHYDE DITHIOACETAL OF CYSTEINEN-TRIFLOUOROACETATE METHYL ESTER

A solution of the 2-pentadecynyl aldehyde (0.3098 g) in dry CH₂ Cl₂ (5ml) was treated with cysteine methylester N-triflouroacetate, freshlyprepared by zinc reduction of the corresponding disulfide (1 g; required0.9667 g), followed by trimethylsilyl chloride (0.15 g). The reactionwas stirred at room temperature for 1 hour. Evaporation of CH₂ Cl₂ invacuo gave a gummy residue which was distributed between CH₂ Cl₂ andwater. The CH₂ Cl₂ phase was separated, and the aqueous phase extractedonce with CH₂ Cl₂. Combined CH₂ Cl₂ extracts were dried over Na₂ SO₄ andevaporated to dryness to provide the crude product which was purified ona coarse silica gel (30 g) column using 20-50% diethyl ether inn-hexane. Yield: 0.6893 g.

EXAMPLE 2 1-BUTANOL, 4,4'-[2-PENTADECYNYLIDENEBIS(OXY)]BIS-, DIBENZOATE

A mixture of 2-pentadecynyl aldehyde diethylacetal (5.0 g),butane-1,4-diol monobenzoate (6.5 g) and p-toluenesulfonic acid (0.2 g)in dry benzene was refluxed with azeotropic removal of ethanol. After 3hours the dark reaction solution was washed with aqueous NaHCO₃, water,then brine. The solvent was removed in vacuo to give crude product (11.0g) as a brownish oil which was used as such in the next reaction.

EXAMPLE 3 1-BUTANOL, 4,4'-[2-PENTADECYNYLIDENEBIS(OXY)]BIS-

The product from Example 2 (4.0 g) was hydrolyzed with 30% KOH inaqueous ethanol (120 ml) by refluxing the reaction mixture for 2 hours.Ethanol was evaporated under vacuum and the residue was washed withwater. The product was extracted with diethyl ether, dried over MgSO₄,filtered and evaporated to dryness in vacuo to give 1.8 g of the productas a yellowish oil.

EXAMPLE 4 BUTANOIC ACID, 4,4'-[2-PENTADECYNYLIDENEBIS(OXY)]BIS-,DIMETHYL ESTER

A. The acetal-diol (1 g; from Example 3) was dissolved in dry DMF (20ml) and treated with pyridinium dichromate (8.2 g). The mixture wasstirred at room temperature for 20 hours, diluted with 200 ml water andextracted with approximately 400 ml diethylether in portions. Dryingover Na₂ SO₄ and evaporation of the ether extract gave the crude diacid.

The reaction was repeated with acetal-diol (0.488 g) in 10 ml DMF and4.1 g pyridinium dichromate. Work-up as above gave the crude diacid.

B. The two reactions from above were combined and treated withdiazomethane (from 6.5 g diazald). Excess diazomethane was removed bycarefully bubbling nitrogen through the solution. Evaporation ofdiethylether gave the crude diester which was chromatographed on TLCgrade silica gel (50 g) using 5% acetone in n-Hexane as eluent. The puredimethylester (0.6813 g) was obtained as a yellowish oil.

EXAMPLE 5 BUTANOIC ACID, 4,4'-[2-PENTADECYNYLIDENEBIS(OXY)]BIS-

The dimethylester (0.5 g; from Example 4) was dissolved in ethanol (10ml) and treated with 10% aqueous NaOH (5 ml). After stirring at roomtemperature for 36 hours, ethanol was evaporated in vacuo, the residuetaken up in water and extracted once with diethylether. The remainingaqueous phase was acidified to pH 1.5 with aqueous oxalic acid andextracted with CH₂ Cl₂. Drying CH₂ Cl₂ extract over Na₂ SO₄ followed byevaporation in vacuo provided the pure diacid as a colorless crystallinesolid, m.p. 62°-63° C. Yield: 0.4496 g.

EXAMPLE 6 1-BUTANOL, 4,4'-[2-NONYNYLIDENEBIS(OXY)]BIS-, DIBENZOATE

A mixture of 2-nonynyl aldehyde diethylacetal (4.4 g), butane-1,4-diolmonobenzoate (8.2 g) and a catalytic amount of p-toluenesulfonic acid indry benzene was refluxed for 3 hours as in Example 2. Work-up as inExample 2 gave the crude product which was purified by passing through aSiO₂ column eluting with hexane and chloroform (1:1) to give 9.0 g ofthe product.

EXAMPLE 7 1-BUTANOL, 4,4'-[2-NONYNYLIDENEBIS(OXY)]BIS-

The product from Example 6 (1.0 g) was hydrolyzed with 30% KOH inaqueous ethanol as in Example 3. The product so obtained was purified bypreparative TLC using 5% methanol in CHCl₃ as eluent. Yield: 0.3 g.

EXAMPLE 8 BUTANOIC ACID, 4,4'-[2-NONYNYLIDENEBIS(OXY)]BIS-

A. The product from Example 7 (0.5 g) was oxidized with pyridiniumdichromate (4.1 g) in 13 ml of dry DMF at room temperature for 2 days.The mixture was diluted with water (350 ml), and extracted withdiethylether (3×100 ml), washed with water, dried (Na₂ SO₄) andfiltered. The solvent was evaporated to give 0.4 g crude diacid whichwas methylated with diazomethane followed by chromatography to give puredimethylester which was hydrolyzed as in Example 5 to give 0.3 g purediacid.

EXAMPLE 9 BENZENEMETHANOL-4,4'-[2-PENTADECYN-1-YLIDENE-BIS(OXY)METHYLENE]BIS

The crude reaction mixture containing benzene methanol-4,4'-dibenzoateester was treated with 100 ml of water, 20 g of KOH and 300 ml ofabsolute ethanol. After stirring the mixture at room temperatureovernight, it was refluxed for one hour. The solvents were thenevaporated, the oily residue was treated with CH₂ Cl₂, washed withwater, and dried over Na₂ SO₄. After evaporation of the solvent, themixture was purified via silica gel chromatography (50% EtOAc/Hexanes).Yield: 8.5 g)

EXAMPLE 10 BENZOIC ACID-4,4'-[2-PENTADECYN-1-YLIDENEBIS(OXY)METHYLENE]BIS

1.7 g of benzoic acid-4,4'[2-pentadecyn-1-ylidenebis(oxy)methylene]bis-dimethyl ester were stirred at room temperature in30 ml of absolute EtOH and 20 ml of 10% aqueous KOH. After two days, thesolvents were evaporated under reduced pressure. The residue was takenin water and acidified with aqueous oxalic acid. The precipitateobtained was filtered, washed with water and dried. Yield: 1.6 g.

EXAMPLE 11 A. METHYL-[4-(OXY)-METHYLACETATE)]-3-OXAOCTADEC-5-YN-1-OATEB. METHYL-[4-(2-OXYETHANOL)]-3-OXAOCTADEC-5-YN-1-OATE

2.0 g of 4-(2-oxyethanol)-3-oxaoctadecen-5yn-1-ol (example 31) in 30 mldry DMF was added in portions to a solution of pyridinium dichromate(PDC) in 70 ml of dry DMF. After stirring at room temperature for twodays, the mixture was poured into water (500 ml). The aqueous solutionwas extracted several times with Et₂ O. The combined extracts werewashed with water and dried over Na₂ SO₄. The crude acid resulting fromthe evaporation of the solvent was treated in Et₂ O at 0° C. with largeexcess of diazomethane solution in Et₂ O. The esterified mixture (2.0 g)was purified by chromatography on TLC grade silica gel:

Fractions 23-28 gave compound (A), 0.13 g

Fractions 75-85 gave compound (B), 0.11 g.

EXAMPLE 12 PENTANOICACID-5,5'-[2-PENTADECYN-1-YLIDENE-BIS(OXY)]BIS-DIMETHYLESTER

A dry DMF solution (50 ml) of1-pentanol-5,5'-[2-pentadecyn-1-ylidene-bis(oxy)]bis (example 14) (3.67g) was added at room temperature to a solution of pyridinium dichromatein 120 ml of dry DMF. After two days the reaction was worked up as inExample 11. The crude reaction mixture was treated at 0° C. in Et₂ Owith large excess of CH₂ N₂. The excess diezomethane was destroyed withglacial acetic acid and the reaction mixture was purified by silica gelchromatography (10% EtOAc/Hexanes). Yield: 0.9 g.

EXAMPLE 13 PENTANOIC ACID-5,5'-[2-PENTADECYN-1-YLIDENE BIS(OXY)]BIS

0.7 g of pentanoic acid-5,5'-[2-pentadecyn-2-ylidenebis(oxy)]bis-dimethyl ester (example 12) was stirred at room temperaturefor 24 hours with 10 ml of absolute EtOH and 10 ml of 10% aqueous KOH.The solvents were then evaporated under reduced pressure. The residuewas taken in water, acidified with aqueous oxalic acid, and extractedseveral times with CH₂ Cl₂. The combined extracts were washed with waterand dried over Na₂ SO₄. Evaporation of the solvent yielded 0.65 g. ofthe title compound.

EXAMPLE 14 1-PENTANOL-5,5'-[2-PENTADECYN-1-YLIDENE-BIS(OXY)]BIS

The crude reaction mixture containing1-pentanol-5,5'-[2-pentadecyn-1-ylidene bis(oxy)]bisdibenzoate ester wasstirred overnight with 150 ml of water and 300 ml of absolute EtOHcontaining 25 g of KOH. After refluxing for three hours, the solventswere evaporated under reduced pressure. The residue was treated with CH₂Cl₂, washed with water and dried over Na₂ SO₄. The reaction mixture waspurified by silica gel chromatography (50% EtOAc/Hexanes). Yield: 4.0 g.

EXAMPLE 15 HEXANOIC ACID, 6,6'-[2-PENTADECYNYLIDENEBIS(OXY)]BIS-

3.5 g of 1-hexanol, 6,6'-[2-pentadecynylidene-bis(oxy)]bis- in 20 ml ofdry DMF was added in portions to a solution of pyridinium dichromate in70 ml of dry DMF at room temperature. After 24 hours, the reaction wasworked up as Example 11. The reaction mixture was purified by silica gelchromatography (first CHCl₃ ; then 5% MeOH/CHCl₃). Yield: 70 mg.

EXAMPLE 16 1-HEXANOL-6,6'-[2-PENTADECYN-1-YLIDENE BIS(OXY)]BIS

The title compound was prepared and purified in similar manner as inExample 14. The starting material was a mixture containing1-hexanol-6,6'-[2-pentadecyn-1-ylidene bis(oxy)]bis dibenzoate ester.

EXAMPLE 17 (±)-1-BENZOYLOXY-6-(4-OXYBUTANE-1-OL)-5-OXAEICOS-7-YNE

3.5 g of benzoyl chloride in 27 ml of CH₂ Cl₂ was added dropwise, over aperiod of three hours, at 0° C. to a solution of1-butanol-4,4'-[2-pentadecyn-1-ylidene bis(oxy)]bis (8.0 g) and drypyridine (15 ml) in 60 ml of CH₂ Cl₂. After the addition, the mixturewas allowed to warm to room temperature and stirred overnight. Themixture was then diluted with CH₂ Cl₂ (400 ml), washed with water, anddried over Na₂ SO₄. After evaporation of the solvent, the reactionmixture (10 g) was purified by silica gel chromatography (10%Acetone/CHCl₃). This material was chromatographed again using CHCl₃ aseluent. Yield 4.2 g.

EXAMPLE 18 (±)-6-(4-OXYBUTAN-1-OL)-5-OXAEICOS-7-YN-1-OIC ACID

2.2 g of product from Example 17 was oxidized and purified as in Example15 (eluent: first CHCl₃, then 1% MeOH/CHCl₃). The product of theoxidation (1.1 g) was hydrolysed and the reaction was worked up as inExample 14. The reaction product was purified by column chromatography(SiO₂ ; eluent: first CHCl₃ ; then 50% CH₃ CN)/CHCl₃ ; then 30%MeOH/CHCl₃). The product obtained from the elution with 30% MeOH/CHCl₃was purified again (SiO₂ ; 5% MeOH/CHCl₃) using the same technique.Yield: 0.16 g.

EXAMPLE 19 6-(4-OXY-METHYLBUTANOATE)-5-OXA-METHYL EICOSANOATE

1.7 g of butanoic acid-4,4'-[2-pentadecyn-1-ylidenebis(oxy)]bis-dimethylester was dissolved in olefin free petroleum ether(60 ml) and hydrogenated in the presence of 10% Pd/C (0.7 g). Afterabsorption of H₂ was complete (3 hours), the catalyst was filteredthrough celite and washed with CH₂ Cl₂. The reaction product (1.6 g)obtained after evaporation of the combined filtrates was purified bysilica gel chromatography (1% acetone in CHCl₃). Yield: 0.8 g.

EXAMPLE 20 BUTANOIC ACID, 4,4'-[PENTADECYLIDENEBIS(OXY)]BIS-

0.65 g of the product from example 19 was hydrolyzed in 12 ml ofabsolute EtOH and 8.1 ml of 10% aqueous KOH as in example 13 to providethe pure diacid.

EXAMPLE 21 (±)-1-BENZOYLOXY-6-ETHOXY-5-OXAEICOS-7-YNE

32 g of ethane-2,2'-[2-pentadecyn-1-ylidene bis(oxy)]bis, 25 g of4-benzoyloxy-1-butanol, and 100 mg of p-toluene sulfonic acid wererefluxed in a dry apparatus in 300 ml of benzene using a Dean-Starktrap. After evaporating 75 ml of solvent, the solution was cooled toroom temperature diluted with CHCl₃, washed with saturated aqueousNaHCO₃, then with water and dried over Na₂ SO₄. The resulting oil (13 g)after evaporation of the solvent was purified by column chromatography(SiO₂) (CHCl₃). The partially purified compound was rechromatographed(SiO₂) (50% Hexanes/CHCl₃). Yield: 1.5 g.

EXAMPLE 22 (±)-6-ETHOXY-5-OXAEICOS-7-YN-1-OL

(±)-1-Benzoyloxy-6-Ethoxy-5-oxaeicos-7-yne was hydrolyzed using the sameprocedure as described for example 14. The reaction mixture was purifiedin the same manner using CHCl₃ as eluent.

EXAMPLE 23 (±)-6-ETHOXY-5-OXAEICOS-7-YN-1-OIC ACID

1.2 g of the product from example 22 in 15 ml of dry DMF was added inportions to a solution of pyridinium dichromate (4.4 g) in 30 ml of dryDMF. The solution was stirred at room temperature for 24 hours, thenpoured into water (300 ml). The aqueous mixture was extracted severaltimes with Et₂ O, the combined extracts were washed with water and driedover Na₂ SO₄. The reaction mixture was purified by column chromatography(SiO₂) (1% MeOH/CHCl₃). The partially purified product (0.54 g) wasfurther purified by preparative thin layer chromatography (SiO₂) (2%MeOH/CHCl₃). Yield: 0.35 g.

EXAMPLE 24 1-PENTANOL, 4,4'-[2-PENTADECYNYLIDENEBIS(OXY)]BIS-

The crude mixture containing 1-pentanol,4,4'-[2-pentdecynylidenebis(oxy)]bis-, dibenzoate ester was hydrolyzedand purified using the same procedure as described for example 14 toprovide the title compound.

EXAMPLE 25 PENTANOIC ACID, 4,4'-[2-PENTADECYNYLIDENEBIS(OXY)]-BIS-

2.6 g of pentanoic acid, 4,4'-[2-pentadecynylidenebis-(oxy)]bis-,dimethyl ester was hydrolyzed using the same procedure as described inexample 13. Yield: 2.4 g.

EXAMPLE 26 5-METHYL-7-(5-OXYHEXANOL)-6-OXAHENEICOS-8-YN-1-OL

The mixture containing5-Methyl-7-(5-oxyhexanol)-6-oxaheneicos-8-yn-1-ol-dibenzoate ester washydrolyzed and purified using the same procedure as described in example14.

EXAMPLE 27 HEXANOIC ACID, 5,5'-[2-PENTADECYNYLIDENEBIS(OXY)]BIS-,DIMETHYL ESTER

The product from example 24 was oxidized, methylated and purified asdescribed in example 12.

EXAMPLE 28 HEXANOIC ACID, 5,5'-[2-PENTADECYNYLIDENEBIS(OXY)]BIS-

The product from example 27 was hydrolyzed using the same procedure asdescribed for example 13.

EXAMPLE 29 CIS-METHYL-6-(4-OXY-METHYLBUTANOATE)-5-OXAEICOS-7-EN-1-OATE

0.4 g of Lindlar catalyst in petroleum ether (10 ml; olefin and sulfurfree) was equilibrated under H₂ at room temperature and atmosphericpressure (containing 5 drops of a 5% solution of quinoline in petroleumether). After four hours, 1.0 g of butanoicacid-4,4'-[2-pentadecyn-1-ylidene bis(oxy)]bis-dimethyl ester in 20 mlof petroleum ether (olefin and sulfur free) was added. The mixtureabsorbed 47 ml of H₂ (theory: 55 ml). The catalyst was then removed byfiltration through "Celite" and washed several times with petroleumether. Evaporation of the solvent yielded 0.9 g of the title compound.

EXAMPLE 30 POTASSIUM-6-(4-OXY-POTASSIUM BUTANOATE-5-OXAEICOS-7-EN-1-OATE

0.6 g of product from example 29 was dissolved in 15 ml of absolute EtOHand 8 ml of 10% aqueous KOH was added. After stirring at roomtemperature for 24 hours, the solvents were evaporated and the residuewas applied as water solution to 65 g of XAD-4 resin column. The columnwas eluted first with water, then with MeOH. The fractions containingthe compound were combined and treated twice with 30% Et₂ O/Hexanes. Thesolvents were decanted and the remaining product dried in vacuo toprovide the title compound.

EXAMPLE 31 ETHANOL, 2,2'-[2-PENTADECYNYLIDENEBIS(OXY)]BIS-

The reaction mixture containing ethanol,2,2'-[pentadecynylidenebis(oxy)]bis-, dibenzoate ester was hydrolyzedand purified using the same procedure as described in example 14.

EXAMPLE 32 ACETIC ACID, 2,2'-[2-PENTADECYNYLIDENEBIS(OXY)]BIS-

0.13 g of acetic acid, 2,2'-[2-pentadecynylidenebis(oxy)]bis-, dimethylester (Example 11) was hydrolyzed using the same procedure described inexample 13. Yield: 0.13 g.

EXAMPLE 33 BUTANOIC ACID,4-[[1-[[3-METHOXY-3-OXO-2(S)-[(TRIFLUOROACETYL)AMINO]PROPYL]THIO]-2-NONYNYL]OXY]-,METHYL ESTER

A solution of the acetal-dimethylester (0.6627 g from example 8-A) indry CH₂ Cl₂ (5 ml) was treated with freshly prepared cysteinemethylester N-triflouroacetamide (from 0.4300 g corresponding disulfide)and the mixture cooled (dry ice/cyclohexanone bath). With stirring andin an atmosphere of N₂, BF₃.Et₂ O (0.05 ml) was syringed in. After 1hour the reaction flask was allowed to stir outside the cooling bath for˜3 minutes and then quenched with dilute (˜7%) NH₄ OH solution.Extractive isolation with CH₂ Cl₂ gave a gummy product (0.9797 g) whichwas chromatographed on TLC grade silica gel (50 g) using 10%acetone/n-Hexane as eluent. Fractions (5 ml each):

41-51 Pure less polar isomer (0.1287 g)

61-81 Pure more polar isomer (0.0831 g) Both isomers were obtained asthick oils.

EXAMPLE 34 BUTANOIC ACID,4-[[1-[[3-METHOXY-3-OXO-2(S)-[(TRIFLUOROACETYL)AMINO]PROPYL]THIO]-2-PENTADECYNYL]OXY]-,METHYL ESTER

A stirred solution of the acetal-diester (1 g; from example 4) dissolvedin dry CH₂ Cl₂ (6 ml) was treated with cysteine methylesterN-triflouroacetamide (freshly prepared from 0.53 g correspondingdisulfide). The mixture was cooled (cyclohexanone/dry ice bath) and thereaction flask was taken out of the cooling bath and let stir for 3-4minutes followed by treatment with dilute (˜7%) NH₄ OH. Extractiveisolation with CH₂ Cl₂ gave a gummy product (1.4618 g) which waschromatographed on TLC grade silica gel (75 g) using 10%acetone/n-Hexane as eluent. Fractions (5 ml each):

50-58 Pure less polar isomer (0.3783 g)

64-78 Pure more polar isomer (0.2626 g) Both isomers were obtained asthick oils.

EXAMPLE 35 BUTANOIC ACID,4-[[1-[(2(S)-AMINO-2-CARBOXYETHYL)THIO]-2-PENTADECYNYL]OXY]-,DIPOTASSIUM SALT (FROM LESS POLAR DIASTEREOISOMER)

The dimethylester (0.3783 g; from example 34, less polar isomer) wassubjected to hydrolysis with 0.13M K₂ CO₃ (100 ml) in MeOH:water (3:1)at room temperature. After ˜36 hours solvents were removed in vacuo andthe crude dipotassium salt so obtained purified on XAD-4 (140 g) column:

Fraction 1, 600 ml--water (discarded)

Fractions 2-5, 400 ml each--methanol

Evaporation in vacuo provided the product as a amorphous solid, 0.1043g.

EXAMPLE 36 BUTANOIC ACID,4-[[1-[(2(S)-AMINO-2-CARBOXYETHYL)THIO]-2-PENTADECYNYL]OXY]-,DIPOTASSIUM SALT (FROM MORE POLAR DIASTEREOISOMER)

The dimethylester (0.3426 g; from example 34, more polar isomer) wassubjected to hydrolysis with 0.13M K₂ CO₃ (100 ml) in MeOH:water (3:1)as in example 35. Work-up and purification on XAD-4 column (140 g)provided in fractions 2-5 (400 ml each, MeOH) the product (0.1049 g) asa amorphous solid.

EXAMPLE 37 BUTANOIC ACID,4,4'-[4E,6Z,9Z-PENTADECATRIEN-2-YNYLIDENE-BIS(THIO)]BIS-

A solution of the product from preparative example IV (1.0 g) and4-mercaptobutanoic acid (1.1 g) in 24 ml of dry CH₂ Cl₂ was cooled to-22° C. (CCl₄ /CO₂) (under N₂). To this was added BF₃ Et₂ O (0.5 ml).The reaction mixture was stirred at this temperature for 2 hours. Themixture was diluted with CH₂ Cl₂ and washed with water. The organicphase was dried (Na₂ SO₄) and concentrated to provide the crude productwhich was purified by passing through 65 g of coarse SiO₂ column, usingCHCl₃ :MeOH:AcOH (990:9:1) as eluent to yield 0.98 g of product.

EXAMPLE 38 HEXANOIC ACID, 6,6'-[2-PENTADECYNYLIDENEBIS(THIO)]BIS-

The product from preparative example II (2.0 g) in CH₂ Cl₂ (15 ml) wastreated with 1-mercapto-5-carbomethoxy-pentane (3.9 g) under N₂ at roomtemperature. To this was added Me₃ SiCl (1.5 ml) and the reaction wasallowed to stir at room temperature for 1/2 hour. The solvent wasremoved under vacuum and the residue was purified on a SiO₂ column withgradient elution (hexane; 2% Et₂ O/hexane; 5% Et₂ O/Hexane; 10% Et₂O/Hexane) to give 3.2 g of product.

EXAMPLE 39 BUTANOIC ACID, 4,4'-[2-PENTADECYNYLIDENEBIS(THIO)]BIS-

The product from preparative example II (1.58 g) and γ-mercaptobutyricacid (2.3 g) in 10 ml of dry CH₂ Cl₂ was treated with Me₃ SiCl (1.0 ml)as in Example 38 to afford 1.35 g of product.

EXAMPLE 40 1-PROPYNL-3,3'-[2-PENTADECYN-1-YLIDENE-BIS(OXY)]BIS

5.0 g of 2-pentadecynal diethyl acetal (preparative example I), 13 ml ofpropargylic alcohol, and 0.2 g of p-toluene sulfonic acid were refluxedin 200 ml of benzene using a Dean-Stark trap provided with an adapterfilled with Dririte. After distilling 170 ml of azeotrope, the residueis diluted with hexanes (200 ml). The organic phase was washed firstwith aqueous NaHCO₃, then with water, dried (Na₂ SO₄) and evaporated invacuo to provide the crude product. It was purified by columnchromatography (SiO₂) eluting first with hexanes (1000 ml), then 3%EtOAC/Hexanes. Yield: 2.4 g.

EXAMPLE 41 1-BUTANOL 4,4'-[(TRIDECYLIDENE)BIS(OXY)]BIS-BENZOATE

To a 3 neck, 100 ml reaction vessel were added: catalytic amount ofρ-toluenesulfonic acid monohydrate (50 mg), 8.54 g of butane 1,4-diolmonobenzoate, and 5 g tridecenal, all in a total 25 ml benzene. Thereaction mixture was heated to reflux with azeotropic removal of water.After ˜2 hours the reaction was cooled, the benzene solution washed withaqueous K₂ CO₃ followed by distilled water. The organic phase was driedover Na₂ SO₄ and evaporated to dryness in vacuo. The crude product soobtained was chromatographed on coarse silica gel (500 g) using 5%acetone in n-Hexane as eluent. Fractions 14 and 15 (200 ml each) wereevaporated in vacuo to provide pure dibenzoate (4.23 g) as a thick oil.

EXAMPLE 42 1-BUTANOL, 4,4'-[TRIDECYLIDENEBIS(OXY)]BIS-

A solution of the dibenzoate (1 g; from example 41) in ethanol (20 ml)was treated with aqueous 10% NaOH solution. An additional 20 ml ethanolwas added to obtain a homogenous solution. After stirring at roomtemperature for ˜48 hours, the reaction was worked up as in example 3 toprovide virtually pure product as a yellowish oil. It was used as suchin the next reaction.

EXAMPLE 43 1-BUTANOIC ACID, 4,4'-[(TRIDECYLIDENE)BIS(OXY)]BIS-DIMETHYLESTER

The diol (1 g; from example 42) was oxidized with pyridinium dichromate(7.33 g) in dry DMF (14 ml) as in example 4A to provide crude diacidwhich was treated with diazomethane as in example 4B. Chromatography ofthe crude dimethylester on TLC grade silica gel (30 g) using 5% acetonein n-Hexane as eluent provided the pure dimethylester (0.28 g) as ayellow oil.

EXAMPLE 44 1-BUTANOIC ACID, 4,4'-[(TRIDECYLIDENE)BIS(OXY)]BIS

A solution of the dimethylester (0.2 g; from example 43) in ethanol wastreated with 10% aqueous NaOH (2 ml) and the mixture refluxed for 4hours. Work-up of the reaction as in example 5 yielded the pure diacid(0.15 g) as a crystalline solid, m.p. 33° C.

EXAMPLE 45 6-[(3-CARBOXYPROPYL)THIO]-7-EICOSYNOIC ACID

A mixture of methyl 6-bromo-7-eicosynoate (3.0 g), methyl4-mercaptobutanoate (1.0 g), Cs₂ CO₃ (2.44 g) in DMF (70 ml) was stirredat room temperature for 2 hours. After dilution with water followed byextraction with Et₂ O afforded 4.0 g crude product which was purified onSiO₂ (200 g) column. Elution with 50% hexane/CHCl₃ gave 1.7 g pureeicosanoate.

The diester (1.42 g) from above was hydrolyzed with 10 ml 10% KOH and 20ml EtOH at room temperature for 5 hours. After work-up as in example 5,the pure diacid was obtained as a solid (1.22 g).

EXAMPLE 46 6-[(5-CARBOXYPENTYL)THIO]-7-EICOSYNOIC ACID

A mixture of methyl 6-bromo-7-eicosynoate, methyl 6-mercaptohexanoate(1.21 g) in 70 ml DMF was treated with Cs₂ CO₃ (2.44 g) as in Example 45to give 1.02 g of methyl-6-[(6-methoxy-6-oxohexyl)thio]-7-eicosynoate.

The diester (0.72 g) from above was hydrolyzed in a similar manner as inExample 45 to give the title compound as a solid (0.53 g).

EXAMPLE 47 6-[(2-CARBOXYETHYL)THIO]-7-EICOSYNOIC ACID

To a stirred slurry of 0.58 g of NaH (50%) in Et₂ O (12 ml) at 0° C. wasadded dry CF₃ CH₂ OH (0.93 ml). After the H₂ evolution had ceased, asolution of triphenylphosphine (1.58 g) in 12 ml of CH₂ Cl₂ was added.After stirring for 10 min, 0.3 ml bromine was added. This mixture wasthen stirred at 0° C. for 1 hour, followed by addition of a solution ofthe product from preparative example VI (1.7 g) andmethyl-3-mercaptopropionate (0.55 ml) in CH₂ Cl₂ (2.5 ml). The mixturewas stirred at room temperature for 7 hours. The reaction was quenchedwith water and extractive isolation with CH₂ Cl₂ yielded 2.5 g crudeproduct. Chromatography on 100 g SiO₂ using 30% hexane in CH₂ Cl₂ aseluent gave 0.66 g of methyl 6-[(3-methoxy-3-oxopropyl)thio]-7-eicosynoate.

The above product (1.3 g) was hydrolyzed with 12.2 ml of 10% NaOH in 25ml EtOH at room temperature for 17 hours. Work-up as in example 5yielded 0.91 g of the product as a yellowish solid.

EXAMPLE 48 POTASSIUM6-[[2-[(TRIFLUOROACETYL)AMINO]ETHYL]THIO]-7-EICOSYNOATE

The product from example 49 (0.5 g) in 40 ml dry MeOH was treated with0.5 g of 5-ethylthiotrifluoroacetate and was stirred at room temperaturefor 1 hour. The MeOH was removed in vacuo to give 0.57 g the titlecompound as a yellowish liquid.

EXAMPLE 49 POTASSIUM 6-[(2-AMINOETHYL)THIO]-7-EICOSYNOATE

Methyl 6-2-(trifluoroacetylethylthio-7-eicosynoate was prepared in amanner similar to Example 47, except thatN-(2-merceptoethyl)trifluoroacetamide was used instead of methyl3-mercaptopropanoate.

The above product (1.0 g) was hydrolyzed with 50 ml of 0.13M K₂ CO₃ inMeOH/H₂ O (3:1) at room temperature for 48 hours and subjected topurification on a XAD-4 (250 g) column to yield 0.56 g of product.

EXAMPLE 50 (±)TRANS-6-[(2-AMINO-2-CARBOXYETHYL)THIO]-5-HYDROXY-7-EICOSYNOIC ACID,DIPOTASSIUM SALT

Hydrolysis of (±)-methyl5-hydroxy-6-[[3-methoxy-3-oxo-2-[(trifluoroacetyl)amino]propyl]thio]-7-eicosynoate(0.23 g) in a manner similar to example 49 provided 0.16 g of the titlecompound.

EXAMPLE 51 (±)-6-[(2-AMINO-3-METHOXY-3-OXOPROPYL)THIO]-7-EICOSYNOIC ACID

(The synthesis of the title compound is described in part E of thisexample.)

Part A

To a solution of dry cyclohexanone (20 g) in dry Et₃ N (125 ml) in dryDMF (125 ml) was added in one portion 61.2 g of t-butyldimethylchlorosilane. The mixture was refluxed under N₂ for two days. Aftercooling to room temperature, the mixture was diluted with Et₂ O, washedwith aqueous NaHCO₃, then with 0.1N HCl, then again with saturatedaqueous NaHCO₃, and finally with water, and dried over Na₂ SO₂. The oil,resulting from the distillation of the solvents, was purified byfractional distillation. Yield: 22 g. B.p.=70°-73° C./4 mm, Hg.

Part B

A solution of 10 g of the product from part A in 150 ml dry CH₂ Cl₂ and15 ml t-butanol was ozonized at -78° C. for 1/2 hour. The excess O₃ waskept in solution for 15 more minutes, then bubbled off with N₂. (CH₃)₂ S(10 ml) was added at -78° C., then the solution was allowed to warm toroom temperature and kept overnight. After evaporation of the solvent,the resulting oil was purified by fractional distillation. Afterdistilling the fraction boiling at 44°-50° C./4 mm Hg, the residue wasused as such.

Part C

14.8 ml of a 3.0 molar solution of EtMgBr in Et₂ O was added at roomtemperature with stirring under N₂ to 10.0 gr of 1-tetradecyne in 20 mlof dry Et₂ O. After the addition, the solution was stirred for anotherhour, then added to a precooled solution (dry ice-acetone bath) of thealdehyde prepared as described in part B (10.0 g) in 75 ml of dry Et₂ O.After the addition, the thick paste formed was allowed to warm to roomtemperature and stirred for one hour; then 75 ml of saturated aqueousNH₄ Cl was added in portions. The organic layer was separated, and theaqueous layer extracted several times with Et₂ O. The combined extractswere washed with water and dried over Na₂ SO₄. The oil resulting fromthe evaporation of the solvent, was purified by fractional distillation.

The fractions distilling between 80° and 100° C. at 3 mm Hg werediscarded. The residue was used as such for part D.

Part D

5.0 g of the product prepared as described in part C was dissolved in 50ml of dry CH₂ Cl₂ and 10 ml of dry pyridine and the solution cooled (icebath). A solution of methanesulfonic anhydride (2.85 g) in 20 ml of dryCH₂ Cl₂ was added dropwise. After the addition, the mixture was let warmup and stirred at room temperature for three hours, then diluted withCH₂ Cl₂. The CH₂ Cl₂ solution was washed twice with water, then withaqueous NH₃ (1:10), then again with water and dried over Na₂ SO₄. Thereaction product (5.4 g) obtained after evaporation of the solvent wasused as such for part E.

Part E

2.0 g of the product prepared as described in part D, t-butanol (7 ml),cysteine methyl ester hydrochloride (1.46 g), and 4 ml of dry Et₃ N weremixed in the order under N₂ at room temperature. After 24 hours, 20 mlof dry CH₂ Cl₂ was added and the mixture stirred for another 24 hours.The solvents were then evaporated, and the reaction mixture was purifiedby column chromatography (silica gel). The column was eluted first withCHCl₃ (3 liters), then with 20% MeOH/CHCl₃. The combined fractionscontaining the compound (2.7 g) were chromatographed again on silicagel. The column was eluted successively with CHCl₃ (1 liter), 5%MeOH/CHCl₃, 10% MeOH/CHCl₃, and 20% MeOH/CHCl₃. The fractions containingthe compound were combined and purified by preparative thin layerchromatography on silica gel [solvent: 10% (MeOH:NH₃)/CHCl₃ (9:1); twoelutions] yield: 0.05 g.

EXAMPLE 52 CYSTEINE, (±)-(1-PENTYL-2-PENTADECYNYL)-N-(TRIFLUOROACETYL)-,METHYL ESTER

Part A

The reaction conditions were the same as in part C of example 51 exceptthat hexanal was used as one of the reactants.

Part B

The reaction conditions were the same as in part D of example 51.

Part C

1.99 g of the product as obtained from part B, tert-butanol (10 ml),2.97 g of cysteine methyl ester N-trifluoroacetate and dry Et₃ N (2.5ml) were racted as described in example 53. The reaction mixture waspurified by column chromatography (silica gel) (CHCl₃). The fractionscontaining the product were combined and purified again as above using50% CHCl₃ /Hexanes as eluent. The pure fractions were combined toprovide the title compound.

EXAMPLE 53 (±)-6-[2-AMINO-3-METHOXY-3-OXOPROPYL)THIO]-7-EICOSYNOIC ACID

1.97 of crude product prepared as described in part D of example 51,tert-butanol (7 ml), N-trifluoroacetyl cysteine methyl ester (2.0 g),and Et₃ N (2 ml) were added at room temperature. The solution wasstirred at room temperature under N₂ for four hours. The solvents werethen evaporated under reduced pressure and the dark oily residueobtained was treated with water and extracted with CHCl₃. The CHCl₃extract was washed with water, dried (Na₂ SO₄) and evaporated todryness. The reaction product (3.6 g) was purified by columnchromatography (silica gel). The column was successively eluted withCHCl₃, and 10% MeOH/CHCl₃. The fractions containing the title compoundwere combined and purified again as above. The column was eluted firstwith CHCl₃, then with 2% MeOH/CHCl₃. The fractions containing the pureproduct were combined and evaporated in vacuo to provide the titlecompound.

EXAMPLE 54 CYSTEINE, (±)-(1-PENTYL-2-PENTADECYNYL)-, POTASSIUM SALT

0.64 g of compound from example 52 was stirred at room temperature underN₂ with 60 ml of 0.13M K₂ CO₃ in MeOH:H₂ O (3:1) for 16 hours. AqueousKOH (0.35 g/ml water) was added and the reaction stirred for 20 hours atroom temperature. The solvents were evaporated under high vacuum. Thesolid residue was treated with water (25 ml) and the pH of the solutionadjusted to 5.2. The mixture was taken in CHCl₃ and the aqueous layerwas separated. The organic layer was washed with water and dried overNa₂ SO₄. Evaporation of the solvent gave the title compound.

EXAMPLE 55 7-EICOSYNOIC ACID, (±)-6-[(2)-AMINO-2-CARBOXYETHYL)THIO]-,DIPOTASSIUM SALT

0.4818 g of product from example 53 was treated with 20 ml MeOH:H₂ O(3:1) and cooled in ice bath under N₂. 0.5 g of KOH in 3 ml of water wasthen added dropwise. The solution was let warm up to room temperatureand stirred for a total of four hours. Aqueous KOH (0.25 g/ml) was addedand after another hour, the solvents were evaporated under reducedpressure. The residue was dissolved in water (10 ml) and applied to anXAD-4 column (145 g). The column was successively eluted with water(10×20 ml), 30% MeOH/H₂ O (6×20 ml), 50% MeOH/H₂ O (5×20 ml) and MeOH(11×20 ml). The methanolic fractions gave 0.28 g of the title compound.

EXAMPLE 56(±)-6-[[2-CARBOXY-2-[(TRIFLUOROACETYL)AMINO]ETHYL]THIO]-7-EICOSYNOICACID

0.4 g of compound prepared according to example 53 was stirred at roomtemperature under N₂ in 57 ml of 0.13M K₂ CO₃ in MeOH:H₂ O (3:1) forfive hours. The solvents were evaporated under high vacuum and theresidue was purified using 250 g XAD-4 resin column in water. The columnwas eluted with water to pH=7, then with 250 ml of 30% MeOH/H₂ O, 500 mlof 50% MeOH/H₂ O, and 100% MeOH. The product (0.16 g) was furtherpurified by preparative thin layer chromatography on SiO₂ (40%MeOH/CHCl₃). Yield: 0.035 g.

EXAMPLE 57(±)-6-[[3-METHOXY-3-OXO-2-[(TRIFLUOROACETYL)AMINO]PROPYL]THIO]-7-EICOSYNOICACID, METHYL ESTER

0.7 g of the product prepared according to example 53 was treated at 0°C. in Et₂ O with large excess of CH₂ N₂ in Et₂ O. Solvent was evaporatedunder N₂ at room temperature. The reaction mixture was purified bycolumn chromatography (SiO₂) (CHCl₃). Yield: 0.22 g.

EXAMPLE 58 PYRAN,(±)TETRAHYDRO-2-[[6-[[6-[(TETRAHYDRO-2H-PYRAN-2-YL)OXY]-HEXYL]OXY]-7-EICOSYNYL]OXY]-

Part A

21 ml (2.85M in Et₂ O) EtMgBr was added dropwise to a solution of1-tetradecyne in 120 ml of dry Et₂ O at room temperature. After theaddition, the brown solution was stirred at room temperature for onehour, then cooled (dry ice-acetone bath). 10.0 g6-[(tetrahydro-2H-pyran-2-yl)oxy]- hexanal in 50 ml of dry Et₂ O wasadded in one portion. The mixture was let warm up to room temperatureand stirred for two hours. 3.5 g NH₄ Cl in 30 ml water was then added.The mixture was diluted with Et₂ O (total volume=750 ml), washed withwater, and dried over Na₂ SO₄. The reaction mixture resulting from theevaporation of the solvent (20 g) was filtered through silica gel (350g) using CHCl₃ as eluent. The product obtained (3.6 g) was used as suchfor part B.

Part B

0.9 g NaH (50% oil dispension) was washed with hexanes under N₂, then 4ml of dry THF was added. 2.66 g of the product from part A was added atroom temperature, and the mixture refluxed under N₂ for three hours.After cooling to room temperature, 3.0 g of1-iodo-6-tetrahydropyran-2-yl-ether was added and the mixture refluxedovernight under N₂. The mixture was then cooled in ice bath and treatedwith water. The solution was taken in CH₂ Cl₂ (300 ml), washed withwater to pH=7 and dried over Na₂ SO₄. The reaction product was purifiedby column chromatography (silica gel) (5% EtOAc/Hexanes). Yield: 1.0 g.

EXAMPLE 59 (±)6-[(6-HYDROXYHEXYL)OXY]-7-EICOSYN-1-OL

1.0 g of 2H-Pyran,tetrahydro-2-[[6-[[6-tetrahydro-2H-pyran-2-yl)oxy]hexyl]oxy]-7-eicosynyl]oxy]-was stirred at room temperature for seven hours with 15 ml methanolcontaining 50 mg of p-toluenesulfonic acid. The solution was keptovernight in the refrigerator, then treated with 3 ml MeOH:aq. NH₃(8:2). After evaporation of the solvents, the resulting oil was taken inCH₂ Cl₂ washed with water (3×50 ml), and dried over Na₂ SO₄. Yield: 0.65g.

EXAMPLE 60 (±)6-[(6-METHOXY-6-OXOHEXYL)OXY]-7-EICOSYNOIC ACID, METHYLESTER

The product from example 59 was oxidized and methylated using the sameprocedure as described in example 11. The reaction mixture was purifiedby column chromatography on silica gel (5% EtOAc/Hexanes).

EXAMPLE 61 (±)6-[(5-CARBOXYPENTYL)OXY]-7-EICOSYNOIC ACID

The product from example 60 (0.2 g) was hydrolysed using the sameprocedure as described in example 13. Yield: 0.195 g.

EXAMPLE 62(-)-METHYL(5R,6S)-5-HYDROXY-6-[(2R)-2-(TRIFLUOROACETYLAMINO)-2-(METHOXYCARBONYL)-ETHYLTHIO]-7-EICOSYNOATEAND(±)-METHYL(5S,6R)-5-HYDROXY-6-[(2R)-2-(TRIFLUOROACETYLAMINO)-2-(METHOXYCARBONYL)-ETHYLTHIO]-7-EICOSYNOATE

A solution of methyl-trans-5,6-epoxy-7-eicosynoate (0.3762 g)(preparative example X) in methanol (0.1 ml) containing Et₃ N (0.8 ml)was treated with cysteine methylester N-trifluoroacetate (0.516 g).After 2 hours the solvents were evaporated in vacuo and the residuedistributed between water and CH₂ Cl₂. The organic phase was thenseparated and the aqueous phase extracted three times with CH₂ Cl₂.Combined CH₂ Cl₂ extracts were washed once with water, dried (Na₂ SO₄)and evaporated to dryness in vacuo to provide a thick yellow oil (1.0097g). The reaction was repeated exactly as above using 1.22 g.trans-epoxide to provide another batch of the product (3.228 g). The twoproducts were combined and chromatographed on TLC grade silica gel using20-30% ethylacetate in n-Hexane as eluent:

A. Less polar isomer 0.94 g, [α]_(D) ²⁶ -10.9°(CHCl₃)

B. More polar isomer 0.66 g, [α]_(D) ²⁶ +22.1°(CHCl₃)

Both isomers were obtained as waxy solids.

EXAMPLE 63(-)-(5R,6S)-5-HYDROXY-6-[(2R)-2-AMINO-2-CARBOXYETHYLTHIO]-7-EICOSYNOICACID DIPOTASSIUM SALT

The less polar dimethylester from example 62 (0.4 g) was stirred with 90ml 0.13M K₂ CO₃ in MeOH:water (3:1) at room temperature in N₂atmosphere. After 36 hours solvents were removed in vacuo (bath temp.40° C.) and the residue obtained subjected to purification on a XAD-4(160 g) column:

Fractions:

water (800 ml)--discarded

1-5 MeOH 0.2783 g amorphous solid

(400 ml) each [α]_(D) ²⁶ -24.6° (MeOH)

EXAMPLE 64(+)-(5S,6R)-5-HYDROXY-6-[(2R)-2-AMINO-2-CARBOXYETHYLTHIO]-7-EICOSYNOICACID DIPOTASSIUM SALT

The more polar dimethylester (0.3 g) was stirred with 66 ml 0.13M K₂ CO₃in MeOH:water (3.1) at room temperature in N₂ atmosphere. After 36 hoursthe reaction was worked up as in example 63 and the product subjected topurification on a XAD-4 (120 g) column:

Fractions:

Water (600 ml)

1-5 MeOH 0.2264 g

(400 ml each) amorphous solid

[α]_(D) ²⁶ +11.9° (MeOH)

EXAMPLE 65 6-HYDROXY-6-(1-TETRADECYNYL)-UNDECANEDIOIC ACID (CRUDE)

A stirred solution of 1-tetradecyne (58.2 g) in 55 ml drytetrahydrofuran (THF) was treated (in argon atmosphere) dropwise withn-BuLi (1.6M in n-Hexane) until 85 ml had been added. A very heavyprecipitation of Li-salt of 1-tetradecyne took place causing difficultyin stirring the reaction mixture. After stirring the reaction mixture inice bath for ˜45 minutes, 6-oxo undecanedoic acid (10.4 g) was added asa concentrated solution in dry THF (50 ml). The reaction mixture wasgradually allowed to warm up to room temperature and stirred for a total15 hours. The pasty reaction mixture was quenched with water andextracted with n-hexane to remove excess 1-tetradecyne. The aqueousphase was adjusted to pH˜2 with aqueous oxalic acid and extracted withCH₂ Cl₂. A crystalline solid not soluble in either phase later found tobe unchanged oxo-dicarboxylic acid was removed by filtration. The CH₂Cl₂ extract was dried (Na₂ SO₄) and evaporated to dryness to provide acrystalline solid. Yield: 6.36 g. This product was used as such in thenext reaction.

EXAMPLE 66 UNDECANEDIOIC ACID, 6-HYDROXY-6-(1-TETRADECYNYL)-,DIMETHYLESTER

The crude diacid from example 65 (0.6 g) was treated with excessdiazomethane as in example 4B and subjected to chromatography on six 1mm thick silica gel plates (solvent system: 20% ethylacetate inn-hexane). The less polar major band was extracted with 20% MeOH/CHCl₃to provide a crystalline solid, m.p. 35° C. Yield: 0.44 g.

EXAMPLE 67 6-HYDROXY-6-(1-TETRADECYNYL)UNDECANEDIOIC ACID (PURE)

A solution of the pure diester from example 66 (0.22 g) in ethanol (5ml) was treated with 10% aqueous NaOH (2.5 ml). The mixture was stirredfor 36 hours at room temperature. Work-up of the reaction as in example5 yielded a crystalline solid, m.p. 65°-66° C. Yield: 0.191 g.

EXAMPLE 68 6-(1-TETRADECYNYL)UNDEC-5Z-ENEDIOIC ACID, DIMETHYLESTER

A solution of the tert. alcohol-dimethylester from example 66 (1 g) inCH₂ Cl₂ (50 ml) was treated with cooling (bath temp 0°-5° C.) and goodstirring with P₂ O₅ (0.8 g). After 1 hour the reaction was quenched withwater. CH₂ Cl₂ phase was separated and the aqueous phase was extractedtwice with more CH₂ Cl₂. The combined CH₂ Cl₂ extract was washed withaqueous NaHCO₃, dried over Na₂ SO₄ and evaporated to dryness to providethe crude product (1.035 g) as a thick oil. It was purified bychromatography on coarse SiO₂ (30 g) using 10% ethylacetate in n-hexaneas eluent (50 ml fractions). The desired 5Z-olefin was obtained as theless polar component. Yield: 0.7564 g. The more polar fraction was amixture of 5Z-(major) and 5E-(minor) olefins (0.2028 g).

EXAMPLE 69 6-(1-TETRADECYNYL)UNDEC- 5Z-ENDIOIC ACID

A solution of the dimethylester from example 68 (0.2 g) in ethanol (5ml) was treated with 10% aqueous NaOH (2.5 ml). The reaction mixture wasstirred for 36 hours and worked up as in example 5 to provide the titlecompound as a crystalline solid, m.p. 47°-48° C. Yield: 0.196 g.

EXAMPLE 70 6-(1-TETRADECYNYL)-UNDEC-5E-ENEDIOIC ACID, DIMETHYLESTER

Dehydration of 7 g. tert. alcohol-dimethylester (from example 66) wasconducted as in example 68. The minor more polar 5E-olefin was isolatedby repeated chromatography on TLC grade silica gel using 10%ethylacetate in-hexane as eluent. The partially purified 5E-olefin(0.149 g) was further purified by preparative thin layer chromatography.

EXAMPLE 71 6-(1-TETRADECYNYL)UNDEC-5E-ENEDIOIC ACID

Hydrolysis of the 5E-olefin-dimethylester (0.16 g) as in example 69 gavethe title compound as a crystalline solid. Yield: 0.15 g.

EXAMPLE 72 UNDECANEDIOIC ACID, 6-FLUORO-6-(1-TETRADECYNYL)-,DIMETHYLESTER

A stirred solution of the 6-hydroxy-dimethylester (1 g; example 66) inCH₂ Cl₂ (5 ml) was cooled (ice bath) and treated withdiethylaminosulfurtrifluoride (DAST) (0.7 ml; excess). After 30 minutesin the ice bath, the reaction was allowed to warm up to roomtemperature. The reaction mixture was stirred for a total of 11/2 hoursfollowed by treatment with dilute NaHCO₃ solution. CH₂ Cl₂ layer wasseparated and the aqueous phase extracted once more with CH₂ Cl₂. Thecombined organic extracts were washed once with water, dried (Na₂ SO₄)and evaporated to dryness to provide a gummy product. It waschromotographed on TLC grade SiO₂ (50 g) using 10% ethylacetate inn-hexane as eluent (˜5 ml fractions). The desired 6-fluoro-dimethylesterwas isolated from the polar fractions 47-52 as a colorless oil. Yield:0.4856 g.

EXAMPLE 73 6-FLUORO-6-(1-TETRADECYNYL)UNDECANEDIOIC ACID

A solution of the fluoro-diester from example 72 (0.22 g) in ethanol washydrolysed with 10% aqueous NaOH (3 ml) as in example 5. Work-up in thesame manner provided the desired diacid as a crystalline solid, m.p.98°-100° C. Yield: 0.2051 g.

EXAMPLE 74 6-FLUORO-6-TETRADECYLUNDECANEDIOIC ACID, DIMETHYLESTER

A solution of the acetylenic product (0.4 g); from example 73) inn-hexane (40 ml) was hydrogenated in the presence of 10% Pd/C (0.1 g).After 15 hours the catalyst was removed by filtration, washed with CH₂Cl₂ and the combined filtrates and washings were evaporated to drynessto provide a thick colorless oil. Yield: 0.4 g.

EXAMPLE 75 6-TETRADECYLUNDECANEDIOIC ACID, DIMETHYLESTER

A solution of the unsaturated diester (0.3 g; example 68) in n-hexane(30 ml) was hydrogenated in the presence of 10% Pd/C (0.1 g) overnight.Catalyst was removed by filtration and washed with CH₂ Cl₂. Evaporationof combined filtrates gave the title compound as a thick colorless oil.Yield: 0.3 g.

EXAMPLE 76 6-TETRADECYLUNDECANEDIOIC ACID

A solution of the diester (0.2 g; from example 75) in ethanol (5 ml) wastreated with 10% aqueous NaOH (2.5 ml) exactly as in example 5 toprovide a crystalline solid, m.p. 48°-50° C.

EXAMPLE 77 6-HYDROXY-6-TETRADECYLUNDECANEDIOIC ACID

A solution of the saturated diester (0.23 g; example 74) in ethanol (8ml) was treated with 10% aqueous NaOH (2.5 ml) as in the previousexperiment. The product after trituration with n-hexane provided acrystalline solid, m.p. 79°-80° C. Yield: 0.1896 g.

EXAMPLE 78 6-(1-TETRADECYNYL)UNDECANEDIOIC ACID

(The synthesis of the title compound is described in part E of thisexample)

Part A

To a solution of 6-(1-tetradecynyl)undec-5Z-enedioic acid dimethylester(1.0 g.; example 68) was added (under N₂) dicobalt octacarbonyl (0.94g.) in dry CH₂ Cl₂ at room temperature. The reaction was stirred for 1hr. followed by removal of CH₂ Cl₂ under N₂ atmosphere.

Part B

A solution of the product from the above reaction (1.5 g.) in drymethanol (25 ml) was added to a slurry of potassium diazodicarboxylate(5.06 g.) in dry methanol (25 ml) in an atmosphere of N₂. The reactionmixture was cooled (ice bath) and a solution of glacial acetic acid (2.7ml) in dry methanol (7.3 ml) was added dropwise. The mixture was stirredin ice bath for three hours. Four additions of potassiumdiazodicarboxylate (as a solid) (3.3 g.) along with glacial acetic acid(1.5 ml) in dry methanol (8.5 ml) were necessary at three hourintervals. After evaporation of methanol in vacuo the residue wasdissolved in CHCl₃, washed with aqueous NaHCO₃, water and dried (Na₂SO₄). Evaporation of the solvent in vacuo left the crude product (1.07g.).

Part C

A portion of the reaction product from above (0.722 g.) was dissolved inacetone (25 ml) and the solution cooled (ice bath). Ceric ammoniumnitrate (3.3 g.) was added in small portions over a period of 30 minuteswith good stirring. The reaction mixture was stirred for an additional15 minutes followed by addition of n-hexane (200 ml). The organic phasewas washed with water, dried (Na₂ SO₄) and evaporated to dryness toprovide the crude dimethylester of the title compound containingunchanged olefinic dimethylester.

Part D

The above mixture was treated with m-chloroperbenzoic acid as describedin preparative example XII. A mixture of the epoxide derived from theunchanged olefinic dimethylester and unreacted dimethylester of thetitle compound was thus obtained. The two products were separated bychromatography on t.l.c. grade silica gel. The pure dimethylester of thetitle compound so obtained was treated as follows.

Part E

A portion (0.1 g.) of 6-(1-tetradecynyl)undecanedioic acid dimethylester(as obtained from Part D) was treated with 10% aqueous KOH as in example13 to provide the title compound. Yield: 0.09 g.

EXAMPLE 79 HEPTANOIC ACID-6,6'-[PENTADECYN-1-YLIDENEBIS(OXY)]-BIS-(2,2-DIMETHYL-1-OXOPROPOXYMETHYL)ESTER

To a stirred solution of heptanoic acid-6,6'-[2-pentadecyn-1-ylidenebis(oxy)]bis (0.5 g) in dry DMF (3 ml) was added dry Et₃ N (0.77 ml).The solution was cooled in an ice bath and a solution of chloromethylpivalate (0.34 ml) was added. The solution was allowed to warm to roomtemperature and stirred in an argon atmosphere for ˜15 hrs. The solventwas evaporated in vacuo, the residue treated with water (20 ml) andextracted several times with ethyl acetate. The combined extracts werewashed with water, dried (Na₂ SO₄) and evaporated to dryness to providea gummy product. The impure product was filtered through a column ofSiO₂ (30 g) using CHCl₃ as eluent. Yield: 0.7 g.

PREPARATIVE EXAMPLE I 2-PENTADECYNAL DIETHYLACETAL

1-Tetradecyne (100 g), (EtO)₃ CH (200 ml) and ZnI₂ (15 g) were heatedtogether (bath temperature 170°-175°) with distillative removal ofethanol (˜90 minutes). The reaction mixture was evaporated in vacuo(bath temperature 80°) to remove excess (EtO)₃ CH. The residue wasdistributed between CH₂ Cl₂ and water. The CH₂ Cl₂ phase was separated,washed with aqueous NaHCO₃, dried (Na₂ SO₄) and evaporated in vacuo toprovide a light brown oil. Yield: 135.4 g. This product was shown to bevirtually pure by TLC and PMR and it was used as such in subsequentreactions.

PREPARATIVE EXAMPLE II 2E-HEXEN-4-YNAL,6,6-DIETHOXY

A mixture of 2-pentadecynal diethyl acetal (4 g) and 10% aqueous H₂ SO₄(60 ml) was refluxed with efficient stirring, for one hour. Anadditional 40 ml dilute H₂ SO₄ was added at this stage and the mixtureheated for another two hours. After cooling, the reaction mixture wasextracted with CH₂ Cl₂, the extract dried (Na₂ SO₄) and evaporated invacuo to provide a yellow oil. Yield: 2.9 g.

PREPARATIVE EXAMPLE III 5-FORMYL-3E-ENE-2-PENTYNAL DIETHYL ACETAL

A stirred solution of diformyl acetylene monodiethylacetal (2.28 g) wastreated in small portions with Ph₃ P═CH.CHO (4.47 g). After stirring for15 hours the solvent was evaporated in vacuo and the dark residuesubjected to chromatography on coarse SiO₂ (100 g) using 5%acetone/n-hexane as eluent. Fractions (100 ml) were collected and thetitle compound was obtained pure from fraction no. 6. Yield: 2.01 g.

PREPARATIVE EXAMPLE IV 4E,6Z,9Z-PENTADECATRIENE-2-YNE ALDEHYDE DIETHYLACETAL

A solution of 3-(Z)-nonene-triphenylphosphonium salt in 20-23 ml of dryTHF was treated with 1.6M BuLi (6.79 ml) and stirred at room temperaturefor 1 hour. The aldehyde (1.68 g, example III) in 3 ml THF was added andallowed to stir for another 3 hours. The reaction mixture was dilutedwith EtOAc and washed with dilute NaHSO₃ solution, brine and dried (Na₂SO₄). Evaporation of the solvent followed by chromatography on SiO₂(eluent 10% Et₂ O in n-hexane) gave the pure product (1.17 g) as ayellow oil.

PREPARATIVE EXAMPLE V (±)METHYL 6-HYDROXY-7-EICOSYNOATE

A cooled solution (ice bath) of the 6-ketone (29.86 g) in methanol (475ml) and water (10 ml) was treated with NaBH₄ (1.27 g) in small portions.After 30 minutes the reaction was diluted with water (50 ml), methanolevaporated in vacuo and the residue distributed between water (50 ml)and CH₂ Cl₂ (100 ml). CH₂ Cl₂ phase was extracted twice with CH₂ Cl₂.The combined CH₂ Cl₂ extracts were dried (Na₂ SO₄) and evaporated todryness to provide the almost pure alcohol as a thick oil (30.23 g). Itwas further purified on coarse silica gel (300 g) using 5% ethylacetate/n-hexane as eluent. Fractions 7-18 (250 ml each) gave the purealcohol. Yield: 21.79 g.

PREPARATIVE EXAMPLE VI (+)METHYL 6(R)-HYDROXY-7-EICOSYNOATE

A solution of (+) α-pinene (1.04 ml; [α]_(D) ²⁶ +47.7°) and9-borabicyclononane (12 ml of 0.5M THF solution; 0.006 mol) was refluxedfor 21/2 hours and cooled to room temperature. With ice bath coolingmethyl 6-oxo-7-eicosynoate (1 g; 0.003 mol) was now added. The mixturewas now stirred under argon at room temperature for 3 days. Acetaldehyde(21 ml) was injected into the solution which was then stirred for 15minutes. The THF and (+) α-pinene were removed in vacuo at 40° (bathtemperature). The remaining yellow product was treated with diethylether(5 ml) to dissolve, followed by addition of ethanolamine (0.38 g; 0.006mol). After stirring at ice bath temperature for 15 minutes, the whiteprecipitate formed was removed by filtration and washed with colddiethylether. The combined filtrate was washed with saturated NaCl,dried (Na₂ SO₄) and evaporated to dryness to provide a thick oil. It waschromatographed on TLC grade SiO₂ (100 g) using 10% ethyl acetate inn-hexane as eluent. Fractions 103-135 (˜15 ml each) gave pure6R-alcohol. Yield: 0.6268 g.

Note: The 6(S)-alcohol of opposite configuration was obtained bysubstituting (+) α-pinene with (-) α-pinene in the above reaction.

PREPARATIVE EXAMPLE VII 2-PENTADECYNE 1-OL

A stirred solution of the aldehyde from preparative example II (16.56 g)in methanol (160 ml) and water (16 ml) was cooled (ice bath) and treatedwith NaBH₄ (1.25 g) in small portions. After ˜10 minutes a crystallineprecipitate separated. Stirring was continued for 30 minutes. Thesolvents were evaporated in vacuo and the residue was distributedbetween CH₂ Cl₂ (˜100 ml) and water (˜50 ml). CH₂ Cl₂ phase wasseparated and the aqueous phase extracted twice with CH₂ Cl₂. Thecombined CH₂ Cl₂ extracts were washed once with water, dried (Na₂ SO₄)and evaporated to dryness to provide a crystalline solid, m.p. 36°-37°C. Yield: 17.8 g.

PREPARATIVE EXAMPLE VIII 1-BROMO-2-PENTADECYNE

A stirred solution of the alcohol (17 g; preparative example VII) in CH₂Cl₂ (500 ml) was treated with CBr₄ (30.19 g). After all CBr₄ haddissolved, the solution was cooled (ice bath) and treated with Ph₃ P(25.87 g). The reaction was worked up after 1 hour as follows: CH₂ Cl₂was evaporated in vacuo and the gummy residue treated with n-hexane. Aprecipitate of Ph₃ P═O so obtained was removed by filtration and washedwith n-hexane. The combined filtrate and washings were evaporated todryness in vacuo and passed through a column of coarse SiO₂ (200 g)using n-hexane (˜2L) as eluent. Evaporation of the n-hexane eluate invacuo (temp. 60°-90°) provided the bromide as a colorless oil. Yield:19.9 g.

PREPARATIVE EXAMPLE IX 2-PENTADECYNE-1-TETRAMETHYLENE SULFONIUM BROMIDE

To a solution of the bromide (18.9 g.; preparative example VIII) in 150ml methanol:water (9:1) was added tetrahydrothiophene (7.56 g). Thereaction mixture was efficiently stirred for 2 days. After washing oncewith n-hexane, the MeOH:water phase was evaporated to dryness and theresidue dissolved in CH₂ Cl₂. The methylene chloride solution wasconcentrated to ˜10 ml and treated with n-hexane until separation ofcolorless crystals took place. The crystals were collected byfiltration. Yield: 13.6 g, m.p. 76°-79° C.

PREPARATIVE EXAMPLE X TRANS-5,6-EPOXY-7-EICOSYNOIC ACID METHYLESTER/CIS-5,6-EPOXY-7-EICOSYNOIC ACID METHYL ESTER

A stirred and cooled solution (bath temperature -25°) of thetetramethylene sulfonium bromide (3 g; preparative example IX) methyl4-formylbutyrate (1.04 g) containing benzyltriethylammonium chloride(0.054 g) in CH₂ Cl₂ (15 ml) was treated with 10M NaOH solution (8.06ml) in one portion. The mixture was efficiently stirred for 1 min. andthen rapidly cooled to -70° (bath temp.). CH₂ Cl₂ layer was decanted outwith a pippette. The frozen aqueous phase was washed 3-4 times with CH₂Cl₂, the combined CH₂ Cl₂ extract and washings were washed with water,dried (Na₂ SO₄) and evaporated to dryness to provide a turbid oil. Theproducts from four such reactions were combined to yield 14.2 g totalcrude product which was chromatographed on TLC grade SiO₂. The columnwas eluted with 50% n-hexane/CHCl₃ (containing 2 ml/1L triethylamine)and ˜6 ml fractions were collected:

Fractions 102-132 Pure trans-epoxide

Fractions 191-205 Pure cis-epoxide

PREPARATIVE EXAMPLE XI (±) METHYL 6-BROMO-7-EICOSYNOATE

This compound was prepared by reaction of methyl 6-(±)-hydroxy-7-eicosynoate (preparative example V) with CBr₄ /Ph₃ P reagentin exactly the same manner as described in preparative example VIII.

Note: By use of the corresponding 6-R, and 6-S alcohols (preparativeexample VI) the optically active (+) and (-) 6-bromo-7-eicosynoates werealso obtained.

PREPARATIVE EXAMPLE XII 5,6-EPOXY-6-(1-TETRADECYNYL)UNDECANEDIOIC ACID,DIMETHYL ESTER

0.19 g. of the product from example 70 was cooled in ice bath andmeta-chloroperbenzoic acid (0.07 g) was added. Additional 0.1 g peracidwas added in two portions after two and three hours period. Two hourslater, the reaction mixture was diluted with CH₂ Cl₂ (180 ml), washedwith aqueous NaHSO₃, aqueous Na₂ CO₃ (3×50 ml), then with water anddried over Na₂ SO₄. The reaction mixture was purified by columnchromatography on silica gel (CHCl₃). The fractions containing the titlecompound were further purified by prepartive thin layer chromatographyon silica gel (20% EtOAc/hexanes). Yield: 0.139 g.

PREPARATIVE EXAMPLE XIII (±)-DIPOTASSIUM5,6-EPOXY-6-(1-TETRADECYNYL)UNDECANEDIOATE

0.37 g. of 6-(1-tetradecynyl)-5,6-epoxyundecanedioic acid dimethyl esterwas stirred at room temperature with 5 ml of absolute EtOH and 1.84 mlof 10% aqueous KOH for 24 hours. The solvents were then evaporated andthe mixture was desalted on a XAD-4 resin (35 g) column. The column waseluted first with water to pH=7, then with 50% H₂ O/MeOH to provide inmethanolic fractions the title compound.

We claim:
 1. A compound having the structural formula II ##STR7## or apharmaceutically acceptable salt thereof, wherein T is a straight orbranched chain alkyl having from 7-15 carbon atoms which may optionallycontain from 1-3 non-cumulative double or triple bonds;U is --C.tbd.C--;V is a straight or branched chain alkylene having from 1 to 4 carbonatoms or is a direct bond; W represents O or S(O)_(m) wherein m is 0, 1or 2; X represents a straight or branched chain alkylene having from 2to 12 carbon atoms which may optionally contain from 1 to 3non-cumulative double or triple bonds and which may be optionallysubstituted with a group --NHR^(a) {wherein R^(a) is hydrogen, alkylhaving from 1 to 6 carbon atoms, COCF₃, CO(CH₂)₂ CH(NH₂)CO₂ H, or SO₂R^(b) and wherein R^(b) is alkyl having from 1 to 6 carbon atoms or CF₃}; Y represents a straight or branched chain alkylene having from 2 to 6carbon atoms which may optionally contain from 1 to 3 non-cumulativedouble or triple bonds; and R² and R³ may be the same or different andare independently selected from CH₂ OR^(c) {wherein R^(c) is hydrogen,carboxylic acyl having from 1 to 6 carbon atoms, tetrahydropyran-2-yl orCOCH₂ CH₂ CO₂ H}, CHO, 2-tetrazolyl, COR^(d) {wherein R^(d) is hydroxy,alkoxy having from 1 to 6 carbon atoms, OCH₂ OC(O)C(CH₃)₃, or NHR^(e)and wherein R^(e) is hydrogen, alkyl having from 1 to 6 carbon atoms orCH₂ CO₂ H} or SO₃ H, with the proviso that at least one of R² and R³ is2-tetrazolyl or carboxyl.
 2. A compound defined in claim 1, havingstructural formula II wherein the substituents T--U--V-- and combined toform the n-1-tetradecyn-1-yl group.
 3. A compound defined in claim 1having structural formula II wherein the substituents R² and R³ may bethe same or different and are COR^(d) wherein R^(d) is defined inclaim
 1. 4. A compound defined in claim 1 having the followingname:(±)-6-(carboxyethylthio)-7-eicosynoic acid;(±)-6-(carboxypropylthio)-7-eicosynoic acid; (+) and(-)-6-(carboxypentylthio)-7-eicosynoic acid;(±)-6-(carboxypentyloxy)-7-eicosynoic acid; potassium6-[[2-[trifluoroacetyl)amino]ethyl]thio]-7-eicosynoate(±)-6-(2-amino-3-hydroxy-3oxopropylthio)-7-eicosynoic acid, dipotassiumsalt; or(±)-6-(3-hydroxy-3-oxo-2-trifluoroacetylamino-propylthio)-7-eicosynoicacid.
 5. A compound having the structural formula II: ##STR8## wherein:T is a straight chain alkylene having from 7-15 carbon atoms;U is--C.tbd.C--; V is a direct bond; W is O or S; X and Y are straight orbranched chain alkylene having from 2 to 6 carbon atoms; and R² and R³are COOH.
 6. A compound as defined in claim 5, wherein the substituentsT--U--V-- are combined to form n--C₁₂ H₂₅ --C.tbd.C--.
 7. A compound asdefined in claim 5 having the name(±)-6-(carboxyethylthio)-7-yneeicosanoic acid; (±)-6-(carboxypropylthio)-7-yne eicosanoic acid;(±)-6-(carboxypentylthio)-7-yne eicosanoic acid; or(±)-6-(carboxypentyloxy)-7-yne eicosanoic acid. 8.6-(carboxypropylthio)-7-eicosynoic acid.
 9. A pharmaceutical compositionfor treating allergic reactions which comprises an anti-allergiceffective amount of a compound as defined in claim 1 in combination witha pharmaceutically acceptable carrier.
 10. A pharmaceutical compositionfor treating inflammation which comprises an anti-inflammatory effectiveamount of a compound as defined in claim 1 in combination with apharmaceutically acceptable carrier.
 11. A pharmaceutical compositionfor treating allergic reactions which comprises an anti-allergiceffective amount of a compound as defined in claim 5 in combination witha pharmaceutically acceptable carrier.
 12. A pharmaceutical compositionfor treating inflammation which comprises an anti-inflammatory effectiveamount of a compound as defined in claim 5 in combination with apharmaceutically acceptable carrier.
 13. A method for treating allergicreactions in a mammal, which comprises administering an anti-allergiceffective amount of composition as defined in claim 9 to said mammal.14. A method for treating inflammation in a mammal, which comprisesadministering an anti-inflammatory effective amount of a composition asdefined in claim 10 to said mammal.
 15. A method for treating allergicreactions in a mammal, which comprises administering an anti-allergiceffective amount of a composition defined in claim 11 to said mammal.16. A method for treating inflammation in a mammal, which comprisesadministering an anti-inflammatory effective amount of a composition asdefined in claim 12 to said mammal.